As the new season begins, Cat Black is conflicted about her full term pregnancy, because the father (Nick Kroll) is 6 years old and has advanced aging disease; the doctors remember Lola who still seems to be dead; Chief has more than professional feelings for the new administrator; Glenn cures cancer.

Cat goes into labor with Little Nicky's baby. Little Nicky's advanced aging disease causes him to take on the tendencies of an old man as the disease begins to kill him. Lola Spratt returns from the hospital to explain that she faked her death, but everyone believes she is a ghost. Blake Downs returns to the hospital, following the failure of his private practice/spin-off. New doctor Valerie Flame takes over narrating duties on the show for Cat Black when complications occur in the birth of she and Nicky's child.

Dr. Maestro asks Dr. Flame to give him a lethal injection so that he can find Dr. Spratt in the spirit world. A creepy EMT wants to show The Chief his "sexy costume.

Dr. Blake's clown brother comes to visit and borrows money from Dr. Blake to pay off his gambling debts, while telling him it's for an operation. A mascot from a local theme park starts suspiciously, repeatedly bringing in children with broken arms for treatment. The hospital is turned into a youth hostel, and Sy gets conned by an attractive young foreign girl.

The staff must choose between saving an old black man and a young white kid. Insult comic Jeffrey Ross brings his child into the O.R., but the staff is more concerned with enjoying his humor than treating his child. Two Star Trek nerds dressed in uniforms (one as a Klingon) visit the hospital.

An episode of TV news magazine News Readers covering the filming of the final episode of Childrens Hospital, complete with behind the scenes looks at the show. Cutter Spindell (who portrays Blake Downs on the show within the show) interferes to save the series, convincing protesters that they're saving an actual children's hospital.

A knife stuck in a boy's chest may not be what it seems; Glenn's cancer cure is threatened by a mysterious visitor, a mind-reading girl visits the coma room.

When the power goes out on the hottest day of the year, sexual tensions boil over among the staff. Blake is date-raped. Dori fries eggs on her boobs.

A hip sexy Rabbi (David Wain) arrives and seduces Valerie, angering Glenn; Sy faces a moral dilemma involving a coffee machine; Lola is confused by a mysterious organ in a cooler.

"Take Your Daughter to Work" day at the hospital ignites a series of conflicts involving a leering child molester (Steve Agee), Chief's sexy daughter (Lizzy Caplan), and an 11 year-old patient whose gender is yet to be determined.

The abortion debate is brought into relief by a visit from a prominent Senator (Ed Begley, Jr.); Owen must decide whether he can treat the 10-year-old who beats him daily; Sy finally faces his alcoholism.